1. The Field of the Invention
The present invention relates to methods for potentiating the immune system in patients having cancer or other diseases. More particularly, the present invention is directed to on-line purification of a patient's blood plasma in order to separate antigens from circulating immune complexes and to subsequently remove the free antigens so that the activity of the patient's lymphocytes may be unblocked.
2. The Prior Art
A normal human body has the ability to develop immunity against foreign substances, such as bacteria, viruses, toxins, and foreign tissues.
An immune response is initiated upon exposure and recognition of a substance as being foreign. (A foreign substance capable of eliciting an immune response is known as an "antigen"). Following this exposure and recognition, the body's lymphoid tissues begin developing specific globulin protein molecules, known as "antibodies," and the lymphoid tissues also produce specifically sensitized lymphocytes that are capable of destroying foreign cells.
It is well known that many types of malignant tumor cells are recognized as being "foreign" and initiate an immune response wherein the patient's body generates specific antibody and circulating cytotoxic lymphocytes. Yet, in cancer patients it is clear that the tumor is not destroyed. Because of this apparent inconsistency, a great deal of effort has been directed to studying the relationship between malignant tumor cells and the immune response.
One result of this research has been the discovery that tumor cells "shed" surface antigens into the patient's circulatory system where they react with specific antibodies, thereby forming an "immune complex." One result of shedding antigens into the patient's bloodstream is that these antigens tie up antibodies and lymphocytes that could otherwise attack the tumor cells. In advanced cancer patients, the level of free antigens in the patient's bloodstream can greatly exceed the capacity of the patient to generate antibody.
However, it has also been discovered that shedding of antigens results in a significant increase in the concentration of immune complexes in the cancer patient's bloodstream. It has been discovered that such an increase in the level of circulating immune complexes and free antigens in the patient's circulatory system suppresses or "blocks" the ability of specific cytotoxic lymphocytes to kill the tumor cells growing in the patient's body. The presence of elevated levels of immune complexes and free antigens are also thought to exert both qualitative and quantitative effects on the immune response by interacting with receptor sites on other types of cells involved in the immune response.
In an attempt to decrease the levels of circulating immune complexes and free antigens in the patient's circulatory system, and hence to "unblock" the patient's immune system, it has become increasingly common to subject seriously ill cancer patients to a series of plasma exchange treatments, commonly called plasmapheresis, wherein a substantial portion of the patient's plasma, containing unwanted circulating immune complexes, is separated from the cellular components of the patient's blood, and is discarded. A volume of previously stored plasma (or of a plasma substitute) approximately equal to the volume of discarded plasma is then infused back into the patient together with the patient's own cellular blood components in an effort to maintain proper blood viscosity, electrolyte balance, and the like. This process of plasma exchange has been successfully used to treat a variety of clinical conditions, such as toxemia, drug overdose, rheumatoid arthritis, and the like, as well as cancer.
However, while capable of removing circulating immune complexes from the patient's circulatory system, and thereby also overcoming the suppressive effects of these complexes on the patient's immune system, the use of plasma exchange treatments on a continuing basis is itself subject to significant disadvantages and dangers that have heretofore generally restricted this treatment for use only on critically ill patients where other alternatives do not exist.
For instance, one major disadvantage of the use of plasma exchange therapy has simply arisen from the lack of availability of replacement plasma. Further, the use of a donor's plasma substantially increases the likelihood of potential complications arising from infection, such as hepatatis, or Acquired Immune Deficiency Syndrome (generally know as "AIDS").
These donor-related problems can be avoided by use of a plasma substitute, i.e., a solution having a suitable electrolyte balance (and, preferably, also to which purified human albumin has been added). However, use of a plasma substitute generally results in a dramatic decrease in the concentration of immunoglobulins in the patient's bloodstream, since a substantial level of immunoglobulins are discarded with the plasma separated during the plasma separation step.
One effect of this reduction is a rebound phenomenon wherein the patient's body vastly increases its production of antibodies. However, a large excess of antibodies tends to mask all the surface antigens of the tumor cells, thereby interfering with the action of cytotoxic lymphocytes. Although some attempts have been made to prevent this rebound phenomenon by administering large replacement doses of immunoglobulins, this approach has not been entirely satisfactory for the same reasons that use of donor plasma is not completely satisfactory.
Additionally, despite great care, a patient subjected to repeated plasma exchange therapy is extremely likely to suffer significant variations in blood viscosity and in fluid and electrolyte balance, depression of immunoglobulins (particularly IgG), clotting disorders, immunological side effects, and/or anemia. In a patient already seriously ill from an advanced tumor, such irregularities are very dangerous. It is believed that such variations may also contribute to metastasis of a previously localized tumor.
Yet another disadvantage of conventional plasma exchange is the inability of that technique to remove antigens that are bound to cells. In cancer patients, it is common for antigens to become bound to the surfaces of lymphooytes, thereby inactivating the lymphocytes. In order to restore the cytotoxioity of these lymphooytes, it has in the past been necessary to conduct a procedure such as removal of the lymphocytes by lymphocytaphoresis followed by either replacement with donor-lymphocytes or "washing off" the antigens from the lymphocytes followed by return of the washed-off lymphocytes to the patient. However, these latter techniques are cumbersome, particularly when it is realized that they must be performed in addition to plasma exchange as set forth above.
In view of the foregoing, it will be appreciated that it would be a significant advance in the art of cancer treatment if improved procedures could be provided for removing immune complexes and free antigens from a patient's circulatory system without causing the serious side effects presently encountered as a result of plasma exchange therapy.